Discovery of catalysts that promote efficient and enantioselective transformations that deliver high value organic molecules is crucial to future advances in the life sciences. For decades, chemists have searched for catalysts that are easily accessible and simple in architecture yet serve as the reliable engine that turns a large number of reaction cycles to generate products within a handful of hours. Catalytic reactions that do not tax our non-renewable resources and do not require expensive reagents, and long hours or recourse to strictly inert conditions are in high demand but scarce.
For nearly half a century, chemists have searched for catalysts that initiate reactions that afford valuable chiral molecules and preferentially afford one product enantiomer (Jacobsen, E. N.; Pfaltz, A. & Yamamoto, H. (eds) Comprehensive Asymmetric Catalysis (Springer, Berlin, 1999)). The importance of ease of access to the large variety of enantiomerically pure organic molecules in biology and medicine, whether discovered in nature or a laboratory, and their derivatives, as well as the inherent economic advantages of a catalytic process has served as the impetus for such longstanding activity (Thayer, A. Chiral catalysts. Chem. Eng. News 83, 40-48 (2005)). Robust reagents that are easily available and devoid of exceedingly toxic metals (e.g., tin or chromium), product isolation and purification conditions that are not severe (e.g., strong reductants or oxidants) and/or costly, are now considered the hallmarks of a desirable transformation. Low catalyst loadings (e.g., ≦1.0 mol %), short reaction times (e.g., ≦8 hours) and the feasibility of reaction at ambient temperature and with a broad range of substrate classes without resorting to rigorous techniques for exclusion of air and moisture are further distinguishing features. Additionally, if transformations generate minimal waste, do not require halogenated solvents, can be promoted by small-molecule catalysts (e.g., ≦350 g/mol−1) that are prepared and purified easily and inexpensively in bulk, and which are stable to air and moisture and do not contain rare and/or precious elements (Nakamura, E. & Sato, K. Managing the scarcity of chemical elements. Nature Mat. 10, 158-161 (2011)), then the transformation belongs to a scarce category. A catalytic method that furnishes sought-after organic molecules and satisfies a portion of the above standards is valuable, but rarely a set of transformations, particularly one that affords a CC bond, meets the large majority of such constraints.
Many biologically active molecules contain one or more nitrogen-substituted carbon stereogenic centers (Kobayashi, S.; Mori, Y.; Fossey, J. S. & Salter, M. M. Catalytic enantioselective formation of CC bonds by addition to imines and hydrazones: A ten-year update. Chem. Rev. 111, 2626-2704 (2011); Yus, M.; González-Gómez, J. C. & Foubelo, F. Catalytic enantioselective allylation of carbonyl compounds and imines Chem. Rev. 111, 7774-7854 (2011); and Puentes, C. O. & Kouznetsov, V. Recent advancements in the homoallylaime chemistry. J. Heterocyclic Chem. 39, 595-614 (2002)). In this context, an efficient route for synthesis of enantiomerically enriched homoallylic amines is of great consequence, since the alkene unit resides within such entities or can be readily manipulated to furnish a notable array of desirable N-containing molecules. Catalytic enantioselective addition of an allyl group to an imine, a direct approach for preparation of enantiomerically enriched homoallylic amines, has thus been the subject of substantial scrutiny. Although a number of innovative strategies have been introduced, a catalytic enantioselective method that possesses most of the abovementioned attributes remains absent. Several approaches require the intermediacy of allylindiums (Kim, S. J. & Jong, D. O. Indium-mediated catalytic enantioselective allylation of N-benzohydrazones using a protonated chiral amine. J. Am. Chem. Soc. 132, 12168-12169 (2010)), prepared in situ from allyl halides and the costly metal, which, at times, must be added in stoichiometric amounts or more (up to 3.0 equivalents; Tan, K. L. & Jacobsen, E. N. Indium-mediated asymmetric allylation of acylhydrazones using a chiral urea catalyst. Angew. Chem. Int. Edn 46, 1315-1317 (2007); Kargo, R.; Takahashi, Y.; Bhor, S.; Cook, G. R.; Lloyd-Jones & G. C.; Shepperson, I. R. Readily accessible, modular, and tunable BINOL 3,3′-perfluoroalkylsulfones: Highly efficient catalysts for enantioselective In-mediated imine allylation. J. Am. Chem. Soc. 129, 3846-3847 (2007)); other protocols entail the use of rare elements (e.g., Pd or Ir salts). Additionally, the following drawbacks are frequently encountered: difficult-to-access or expensive chiral ligands (Wada, R.; Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai, M. & Shibasaki, M. Catalytic enantioselective allylation of ketoimines J. Am. Chem. Soc. 126, 7687-7691 (2006)), relatively high catalyst loadings (e.g., ≧10 mol %, Lou, S.; Moquist, P. N. & Schaus, S. E. Asymmetric allylboration of acyl imines catalyzed by chiral diols. J. Am. Chem. Soc. 129, 15398-15404 (2007)), long reaction times (e.g., 12 hours, Chakrabarti, A.; Konishi, H.; Yamaguchi, M.; Schneider, U. & Kobayashi, S. Indium(I)-catalyzed asymmetric allylation, crotylation, and α-chloroallylation of hydrazones with rare constitutional and high configurational selectivities. Angew. Chem. Int. Edn 49, 1838-1841 (2010)), low or elevated temperatures (e.g., −50 or 100° C.; Vieira, E. M.; Snapper, M. L. & Hoveyda, A. H. Enantioselective synthesis of homoallylic amines through reactions of (pinacolato)allylborons with aryl-, heteroaryl-, alkyl-, or alkene-substituted aldimines catalyzed by chiral C1-symmetric NHC—Cu complexes. J. Am. Chem. Soc. 133, 3332-3335 (2011); Naodovic, M.; Wadamoto, M. & Yamamoto, H. Enantioselective Ag-catalyzed allylation of aldimines. Eur. J. Org. Chem. 2009, 5129-5131 (2009)), necessity for highly activated aldimines (e.g., glyoxylate derived; Ferraris, D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J.; Ryzhkov, L.; Taggi, A. E. and Lectka, T. Catalytic, enantioselective alkylation of α-imino esters: The synthesis of normatural α-amino acid derivatives. J. Am. Chem. Soc. 124, 67-77 (2002); Hamada, T.; Manabe, K. & Kobayashi, S. Angew. Chem. Int. Edn 42, 3927-3930 (2003)), narrow substrate range (e.g., low yield and/or e.r. when alkyl-substituted), imine protecting groups removal of which demands pricey reagents (e.g., SmI2; Fujita, M.; Nagano, T.; Schneider, U.; Hamada, T. & Kobayashi, S. Zn-catalyzed asymmetric allylation for the synthesis of optically active allylglycine derivatives. Regio- and Stereoselective formal addition of allylboronates to hydrazono esters. J. Am. Chem. Soc. 130, 2914-2915 (2008)) or harsh conditions (e.g., strong alkylating (Ding, H. & Friestad, G. K. Trifluoroacetyl-activated nitrogen-nitrogen bond cleavage of hydrazines by samarium(II) iodide. Org. Lett. 6, 637-640 (2004)) or reducing agent (Lou, S.; Moquist, P. N. & Schaus, S. E. Asymmetric allylboration of acyl imines catalyzed by chiral diols. J. Am. Chem. Soc. 129, 15398-15404 (2007))), the need for allyltins (Aydin, J.; Kumar, S.; Sayah, M. J.; Wallner, O. A. & Szabó, K. J. Synthesis and catalytic application of chiral 1,1′-bi-2-napthol and biphenanthrol-based pincer complexes: Selective allylation of sulfonimines and allyl stannane and allyltrifluoroborate. J. Org. Chem. 72, 4689-4697 (2007)) or moisture-sensitive allyl-containing agents (Lou, S.; Moquist, P. N. & Schaus, S. E. Asymmetric allylboration of acyl imines catalyzed by chiral diols. J. Am. Chem. Soc. 129, 15398-15404 (2007)). The corresponding additions to ketones represent an equally important class of transformations, and a particularly noteworthy group of substrates in this regard are isatins (Ruiz-Sanchis, P.; Savina, S. A.; Albericio, F. & Álvarez, M. Structure, bioactivity and synthesis of natural products with hexahydropyrrolo[2,3-b]indole. Chem. Eur. J. 17, 1388-1408 (2011)). Such reactions offer access to enantiomerically enriched 3-hydroxy-2-indoles, which are imbedded within several alkaloids of substantial biological significance (Ishikura, M. & Yamada, K. Simple indole alkaloids and those with a nonrearranged monoterpenoid unit. Nat. Prod. Rep. 26, 803-852 (2009)). There is evidence that the absolute configuration of the tertiary hydroxyl unit impacts biological activity (Peddibhotla, S. 3-Substituted-3-hydroxy-2-oxindole, an emerging new scaffold for drug discovery with potential anti-cancer and other biological activites. Curr. Bioact. Compd. 5, 20-38 (2009)). Nevertheless, only a small number of reports address catalytic enantioselective allyl additions to isatins, and similar limitations, including the need for allyltins and precious metal salts (Itoh, J., Han, S. B. & Krische, M. J. Enantioselective allylation, crotylation, and reverse prenylation of substituted isatins: Iridium-catalyzed CC bond-forming transfer hydrogenation. Angew. Chem. Int. Edn 48, 6313-6316 (2009)), moderate selectivities, and difficult-to-prepare catalysts exist here as well.
Previous research, dominated by reactions involving exceptionally nucleophilic and thus sensitive allylmetal intermediates requires rigorously anhydrous and/or oxygen-free conditions (Vieira, E. M.; Snapper, M. L. & Hoveyda, A. H. Enantioselective synthesis of homoallylic amines through reactions of (pinacolato)allylborons with aryl-, heteroaryl-, alkyl-, or alkene-substituted aldimines catalyzed by chiral C1-symmetric NHC Cu complexes. J. Am. Chem. Soc. 133, 3332-3335 (2011)). Furthermore, with substituted allylmetal intermediates, high diastereoselectivity is either not observed (Tan, K. L. & Jacobsen, E. N. Indium-mediated asymmetric allylation of acylhydrazones using a chiral urea catalyst. Angew. Chem. Int. Edn 46, 1315-1317 (2007); Vieira, E. M.; Snapper, M. L. & Hoveyda, A. H. Enantioselective synthesis of homoallylic amines through reactions of (pinacolato)allylborons with aryl-, heteroaryl-, alkyl-, or alkene-substituted aldimines catalyzed by chiral C1-symmetric NHCCu complexes. J. Am. Chem. Soc. 133, 3332-3335 (2011)), or only one of the two possible diastereomers can be accessed (Itoh, J., Han, S. B. & Krische, M. J. Enantioselective allylation, crotylation, and reverse prenylation of substituted isatins: Iridium-catalyzed CC bond-forming transfer hydrogenation. Angew. Chem. Int. Edn 48, 6313-6316 (2009)). One example of a catalytic “all-boron” allyl addition protocol proceeds less readily, requiring higher catalyst amounts and longer reaction times, than when an allylmetal is involved (e.g., 15 mol % loading and 36 hours). Similar to cases that proceed via an allylmetal, reactions with the latter metal-free catalyst and E- or Z-disubstituted allylborons deliver the same product diastereomers (Lou, S.; Moquist, P. N. & Schaus, S. E. Asymmetric allylboration of acyl imines catalyzed by chiral diols. J. Am. Chem. Soc. 129, 15398-15404 (2007)).